CHEMISTRY AND BIOLOGY OF PLATINUM ANTICANCER DRUGS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The platinum compound cis-[Pt(NH3)2(pyridine)Cl]Cl has previously demonstrated potent cytotoxicity in a screen against in vivo murine tumor models. This result is of particular interest because this compound forms only monofunctional adducts with DNA, and thus does not follow the classic structure-activity relationship for platinum anti-tumor agents that requires two leaving groups to be present in a cis conformation. Recent data has shown this compound may be recognized by cellular repair proteins and block transcription in a manner that is unique to monofunctional platinum compounds, but similar to cisplatin and other bifunctional platinum compounds. It is therefore desirable to obtain a detailed structural model of this platinum-DNA adduct, which may help to explain the unexpected activity of the complex. We have recently crystallized a DNA dodecamer duplex containing a single {Pt(NH3)2(pyridine)}-dG adduct, and collected X-ray diffraction data to 2.17 ¿. The global structure of the DNA is quite different from that of DNA containing a platinum intrastrand d(GpG) cross-link. The latter platinated duplex is bent by ~40¿ towards the major groove at the site of the cross-link, yet the monofunctional platinumdG lesion causes no significant distortion of the double helix. Like the cisplatin intrastrand cross-link, however, the monofunctional adduct creates a distorted base pair step to the 5' side of the platinum site that may be correlated to antitumor activity. These data allow us to reevaluate the structure-activity relationship of platinum anticancer agents to include monofunctional, "non-classical" platinum compounds, and to use this evidence to work towards elucidating the molecular mechanism of action of a unique platinum complex that may be able to be used in treatment of colorectal cancer.